Blast exposure is the leading cause of traumatic brain injury among U.S. forces deployed to Afghanistan and Iraq, yet alarmingly little is known about the pathological consequences of blast exposure because so few human brains have been studied. Our studies of over 500 brains of contact sport athletes and military veterans exposed to blast and concussive injury have shown that both blast and concussive impact injuries are associated with microvascular dysfunction, neuroinflammation, astrocytosis, hyperphosphorylated tau (ptau) deposition and the development of chronic traumatic encephalopathy (CTE), a posttraumatic neurodegeneration. CTE is defined pathologically by the perivascular accumulation of hyperphosphorylated tau (ptau) protein and results in progressive decline in cognitive, behavioral and mood function. There is a critical need to comprehensively examine more veteran cases of blast injury in order to determine the precise pathobiology underlying the late-effects of these injuries and to develop biomarkers to detect the specific, yet evolving, molecular, cellular, and anatomical brain changes induced by blast exposure. Given that 300,000 military veterans have been exposed to blast, there is urgency to recruiting brain donation from these veterans and analyzing the effects of blast on critical brain processes. Understanding the neuropathology of blast- induced brain changes will identify ways to detect these alterations during life and to monitor the development of posttraumatic neurodegeneration and CTE. In this application, we will use the largest neuropathologically confirmed autopsy cohort of veterans exposed to blast and concussive injury, in conjunction with a robust recruitment effort to dramatically increase the number of brain donors, to determine the relationship between blast exposure and neuroinflammation, blood brain barrier leakage, astrocytic degeneration, loss of the glymphatic clearance network and ptau pathology. We will use cutting edge neuropathological techniques including quantitative immunohistochemistry, multiplex immunofluorescence, quantitative polymerase chain reaction (qPCR) expression analysis, enzyme-linked immunosorbent assay?s (ELISA), in situ hybridization (ISH) and gene expression assays in veterans with a history of blast injury, veterans and contact sport athletes with a history of concussive impact injury and veteran controls to gain new insights into the molecular mechanisms underlying blast-induced posttraumatic neurodegeneration and CTE. We will also test whether APOE?4 and TMEM106b haplotype status modify these effects. This research will pave the way towards identifying novel biomarkers for detection and targets for early therapeutic intervention in blast-induced posttraumatic neurodegeneration and CTE. Understanding the fundamental pathophysiology underlying microvasculopathy, inflammation, astrocytosis, aquaporin loss and accelerated ptau pathology after exposure to blast and concussive impact injury will help identify novel biomarkers to detect and treat CTE and posttraumatic neurodegeneration in living veterans.